CNS degenerative diseases are among the most dreaded afflictions from which older people frequently suffer. The most common of these neurodegenerative disorders is Alzheimer's disease. Studies on the etiologies of both the familial and sporadic forms of Alzheimer's disease have been frustratingly slow in part due to our lack of both knowledge about its molecular pathogenesis and suitable animal models. In contrast, the availability of animal models for neurodegenerative diseases caused by prions has led to relatively rapid advances. Indeed, prions diseases have become the most well understood CNS degenerative disorders of delayed onset and they are the focus of this proposal. In humans, prion diseases generally occur in older adults but the mechanism governing their time of onset is unknown. We plan to identify neurotransmitter/receptor systems that malfunction in both the genetic and infectious forms of prion diseases. Alterations in brain lipids, glycolipids and activated glycolipids and activated glycolipids will be measured since their regulation is intimately linked to the synthesis of the prion protein (PrP) which is a sialoglycoprotein that carries a glycoinositol phospholipid (GPI). Measurements of Ca++ flux and compartmentalization will be studied in scrapie-infected cultured cells where abnormalities in Ca++ metabolism have already been identified. Alterations in Ca++ metabolism have been demonstrated in recent years to feature prominently in CNS dysfunction and neuronal death. While considerable progress has been made in deciphering the cellular processes which govern prion incubation times, relatively little is known about the molecular mechanisms responsible for distinct prion isolates or "strain". Transgenic mice crossed with mice in which the murine PrP gene has been ablated will be used to define those factors which govern the phenotype of the "infectious" prions. Physical studies designed to search for a hypothetical cellular RNA which has been proposed to modify the properties of PrPSc will be performed as will studies on the conformation of PrPSc in two isolates exhibiting different incubation times. These proposed studies address the molecular mechanism responsible for the pathogenesis of both the infectious and genetic forms of prion diseases and by inference the most common form of CJD which is sporadic. The diverse skills, talents and backgrounds of the investigators in the proposed program offer an unusual opportunity to attack the molecular mechanisms underlying the neuropathogenesis of prion diseases. Elucidation of the mechanisms by which brain cells cease to function and die in prion diseases after a long delay may offer approaches to under standing how neurons develop, mature, continue to transmit signals for decades and then become senescent. Moreover, understanding prion diseases may give valuable new insights with respect to the etiologies of more common CNS degenerative disorders afflicting older people, including Alzheimer's disease.